The small vessels of the brain play key roles in both age-related vascular cognitive impairment and clearance of the -amyloid peptide (A). Cerebrovascular deposition of A as cerebral amyloid angiopathy (CAA) sets up a potentially self-reinforcing mechanistic loop in which CAA-related vascular injury and dysfunction lead to reduced A clearance and progressively worse A deposition, CAA, and Alzheimer disease pathology. We propose a systematic, multidisciplinary analysis of the mechanisms underlying A-related cerebrovascular injury, vascular dysfunction, and impaired perivascular clearance in human CAA and transgenic mouse models. Specific experiments, each designed to translate from mouse models to reliably diagnosed human CAA, focus on the effects of CAA on cerebral small vessel compliance, physiologic reactivity, and their relationship to focal brain lesions (SA1), the effects of altered physiology on A clearance and accumulation (SA2), and the effects of CAA on gene expression in cerebrovascular endothelium and smooth muscle (SA3). The proposal builds on the applicants' long record of successful mutual collaborations and their internationally recognized expertise and leadership in noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of cerebrovascular gene expression in control and disease states. The proposal also builds on a wide range of cutting-edge methodologic advances such as ultrahigh-field functional MRI, serial molecular A imaging, intravital multiphoton microscopy, vasculomic analysis, and laser-capture microdissection of post-mortem tissue. Successful completion of the proposed highly translational experiments will determine A's vascular effects at the molecular, single-vessel, and whole-brain levels, establish their relevance to clinical disease, and yield entirely new and promising approaches to interrupting the vicious cycle of vascular injury and reduced A clearance key to the propagation of CAA and Alzheimer's disease.